3-halo-delta3-a-norandrostene-2, 17-diones



United States Patent Oil 3,881,824 Patented Jan. 2, 1863 ice 3,361,824 3-HALO-A -A-NRANDR0STENE-2,17-DI0NES Seymour D. Levine, Princeton, N.J., assignor, by mesne assignments, to E. R. Squibb & Sons, Inc., New York,

N .Y., a corporation of Delaware No Drawing. Filed Mar. 8, 1965, Ser. No. 438,042 2 Claims. (Cl. 260-586) ABSTRACT OF THE DISCLOSURE This invention relates to 3-halo-17-oxyengated A A- norandrostene-Z-ones. The compounds are prepared by treating the corresponding 3,5-epoxy-l7 oxygenated A- norandrostane-Z-ones with a hydrogen halide. The compounds are physiologically active, possessing anti-androgenic activity.

This invention relates to new chemical compounds and more particularly to new steroidal substances and their method of preparation.

The new steroids of this invention can be depicted by the Formula I:

wherein R is as hereinbefore defined, with hydrogen peroxide to yield, inter alia, new intermediates of this invention of the Formula III:

III

wherein R and R are as hereinbefore defined.

These new intermediates are then interacted with a hydrogen halide, preferably hydrogen chloride and hydrogen bromide, to yield the final products of this invention of the Formula I.

The suitable starting steroidal materials are A-nortestosterone and 17a-methyl-A-nortestosterone. These compounds on treatment with hydrogen peroxide yield, inter alia, 3B,5/8-epoxy-A-norandrostane 2 one 17p? 01 and 3,8,5B-epoxy-17a-methyl-A-norandrostane-2-one-17p 01, respectively. To prepare the other new intermediates of Formula III of this invention, either 3B,5,8-epoxy-A-norandrostane-Z one 17,8 01 is oxidized by treatment with chromium trioxide to yield 35,5[3-epoxy-A-norandrostane- 2,17-dione; or 3,8,SB-epoxy-A-norandrostane-Z-one-17,8-01 or 3,8,5fi-epoxy-17a-methyl-A-norandrostane-Z-one 17,8- 01 is treated with an acid anhydride or acyl halide of the desired acid to yield the l7fl-ester derivative. Among the suitable acid anhydrides and acyl halides, those preferred are the anhydrides or acyl chlorides of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alk-anoic acids (e.g., acetic, propionic, butyric and hexanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic acid), the monocyclic aryl lower alkanoic acids (e.'g., phenacetic and fi-phenylpropionic acid), the monocyclic cycloalkanecar boxylic acids, the monocyclic cycloalkenecarboxylic acids, the monocyclic cycloalkane lower alkanoic acids, and the monocyclic cycloalkane lower alkenoic acids.

The resulting compounds of Formula II are then reacted with a hydrogen halide to yield the final products of this invention. If a free 17 3-hydroxy starting material is used when R is hydrogen and the reaction is carried out in the presence of glacial acetic acid as the solvent, the compound obtained is in the form of its 17-acetate. If, however, the reaction is conducted in an inert solvent, such as chloroform and/ or ethanol, then the final product is obtained in its free I7B-hydroxy form.

The following examples illustrate the invention (all temperatures being in Centigrade):

EXAMPLE 1 3,8,5fl-epoxy-A -n0randr0stane-2-0ne-1 71301 A solution of 2 g. of A-nortestosterone in 20 ml. of methanol is treated with 8 ml. of 30% hydrogen peroxide solution and 4 ml. of aqueous 4 N sodium hydroxide solution and left at room temperature for 16 hours. The reaction mixture is diluted with water and extracted five times with ether. The ether extracts are Washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue using silica gel as the adsorbent and chloroform containing 2% methanol as the developing solvent gives two bands detectable with iodine which are eluted with ethyl acetate. Crystallization of the residue from the less polar band from isopropyl ether gives 35,5;3-epoxy-A-norandrostane 2-one-17fi-ol having a melting point of about 143.5- 144.5 The analytical sample is prepared by recrystallization from isopropyl ether, M.P. about 144-145 [(11 +102 (chf.);

EEL 2.83 and 5.77;;

Si(CH 9.22 (8., 18-Me), 8.82 (5., 19-Me), 7.88 (5., 1CH2), 6.87 (m, 3-H) and 6.39 (m., 17H).

Analysis.-Oalcd. for C18H26O3 (290.39): C, 74.44; H, 9.03. Found: C, 74.35; H, 8.85.

EXAMPLE 2 17a-methyl-3 8JB-epoxy-A -n0randr0stane-2-one-1 7 ,B-ol

Following the procedure of Example 1 but substituting 0 17a-methyl-A-nortestosterone for the A nortestosterone,

there is obtained 17 a-methyl-3 18,5/3-ep0xy A norandrostane-2-one-17/3-ol.

3 EXAMPLE 3 3 5,5 5-epoxy-A -norandrsttzne-2,1 7 -dz'0ne A solution of 250 mg. of 35,55-epoxy-A-norandrostane- 2-one-175-ol in 10 ml. of acetone is treated dropwise with stirring with a slight excess of chromium trioxide-sulfuric acid. Ethanol is added to decompose excess oxidizing agent and the acetone layer is decanted. The inorganic residue is washed with additional acetone. The acetone fractions are combined and evaporated to dryness to give 35,5 -epoxy-A-norandrostane-2,17-dione.

EXAMPLE 4 3 5,5 5-2 poxy-A -n0randr0stan e-Z-one-l 75-01 acetate A mixture of 100 mg. of 35,55-epoxy-A-norandrostane- 2-one-175-ol, 0.1 ml. of pyridine, and 1 ml. of acetic anhydride is left at room temperature for 16 hours. The reaction mixture is poured into ice-Water and extracted with ether. The ether extracts are washed with a saturated sodium bicarbonate solution, 8% salt solution, dried over sodium sulfate and evaporated to dryness to yield 35,55- epoxy-A-norandrostane-Z-one-l75-01 acetate.

IIn a similar manner, by substituting any other acid anhydride for the acetic anhydride in the procedure of Example 4, the corresponding ester is formed.

EXAMPLE 5 1 7a-methyl-3 5,5 5-ep0xy-A -n0randr0stane-Z-one-I 75-0 l acetate A solution of 0.0033 ml. of perchloric acid in 0.3 ml. of acetic anhydride is added to 500 mg. of 17a-methyl-35,55- epoxy-A-norandrostane-Z-one-175-01 in ml. of acetic anhydride. The reaction mixture is stirred 'at room temperature for 30 min. and then poured into ice-Water and extracted with chloroform. The chloroform extracts are washed with a saturated sodium bicarbonate solution, 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17a-methyl-35,55-epoxy-A-norandrostane- 2-one-17 5-01 acetate.

In a similar manner, by substituting any other acid anhydride for the acetic anhydride in the procedure of Example 5, the corresponding ester is formed.

EXAMPLE 6 3 -ch l0r0-A -A -n0randr0sten e-Z-one-I 75-0l acetate A solution of 150 mg. of 35,55-epoxy-A-norandrostane- 2-one-l75-ol in 10 ml. of glacial acetic acid is saturated with hydrogen chloride gas and refluxed for 10 hours. The reaction mixture is concentrated and the residue taken up in chloroform. The chloroform solution is washed with saturated sodium bicarbonate solution, 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 3-chloro-A -A-norandrostene-2-one 175 o1 acetate. The analytical sample is prepared by recrystallization from acetone-hexane, M.P. about 175-177; +26

REE; 5.80 and 6.13;).

ALtOI-I 246 my (13,400); 'rSl(CH 9.14 (s., 18-Me), 8.78 (s., 19-Me), 7.95 (s., 17-acetate), and 5.39 (m., 17H).

Analysis-Calm. for C2QH2703C1 (350,87); C, 68.46; H, 7,76. Found: C, 68.35; H, 7.77.

' 4 EXAMPLE 7 3-chl0r0-A -A -n0randr0stene-2-0ne-1 -0l A solution of mg. of 35,55-epoxy-A-norandrostane- 2-one-175-ol in 9 ml. of chloroform and 1 ml. of ethanol is saturated with hydrogen chloride gas and refluxed for 8 hours. The reaction mixture is washed with saturated sodium bicarbonate solution, 8% salt solution, dried over sodium sulfate and evaporated to give 3-chloro-A -A-norandrostene-2-one-175-ol.

Similarly, by substituting 17-esters for the free 17-hy- A droxy compound in Example 7, the corresponding esters of 3-chloro-A -A-norandrostene-2-one-175-01 are formed.

EXAMPLE 8 1 7ot-methyl-3-chlor0-A -A -n0randr0stene-2-0ne-1 75-01 Following the procedure in Example 7 but substituting l7a-methyl-35,55-epoxy-A-norandrostane-Z-one- 01 for 35,55-epoxy-A-norandrostane-Z-one 175 01 there is obtained 17a-methyl-3-chloro-A -A-norandrostene-Z-one- 175-01.

EXAMPLE 9 1 7a-methyl-3-chlor0-A -A -n0ran'drostene-2-0ne-1 75-0l- 1 7-acetate Following the procedure of Example 7, but substituting 17a-methyl 35,55-epoxy-A-norandrostane-Z-one 175 ol acetate for the steroid reactant, there is obtained 17ozmethyl-3-chloro-A -A-norandrostene-Z-one-175-ol 17-acetate.

EXAMPLE 1O 3-chl0r0-A -A -n0randrostene-2 ,1 7-di0ne Following the procedure of Example 7, but substituting 35,55-epoxy-A-norandrostaneQ,17-dione for the steroid reactant, there is obtained 3-chloro-A -A-norandrostene- 2,17-dione.

EXAMPLE 11 3-br0m0-A -A -n0randr0stene-2-one-1 75-01 acetate Following the procedure of Example 6 but substituting a hydrogen bromide gas for the hydrogen chloride gas, there is obtained 3bromo-A -A-norandrostene-2-one-175- ol acetate.

Similarly, by substituting l7a-methyl-3 5,5 5 epoxy A- norandrostane-Z-one-l75-01 or 35,55-epoxy-A- norandrostane-2,17-dione for the 35,55-epoxy-A-norandrostane-2 one-175-ol in the procedures of Examples 6 and 7 and-hy References Cited Chemical Abstracts, 1961: 55: 26030.

Shawv et al.: J. of Chem. Society, 1955, 34, pp. 3549- 3551.

Mancera et 211.: Can. J. Chem., vol. 37, 1959, pp. 1785- 1787.

LORRAINE A. WEINBERGER, Primary Examiner,

RICHARD K. JACKSON, Examiner. IV GARNER; i qrt Exqmin n 

